D2-LIKE RECEPTOR ACTIVATION DOES NOT INITIATE A BRAIN DOCOSAHEXAENOIC ACID SIGNAL IN UNANESTHETIZED RATS. The polyunsaturated fatty acid, docosahexaenoic acid (DHA), participates in neurotransmission involving activation of calcium-independent iPLA2, which is coupled to muscarinic cholinergic and serotonergic neuroreceptors. Drug induced activation of iPLA2 can be measured in vivo with quantitative autoradiography using 14C-DHA as a probe. The present study used this approach to address whether a DHA signal is produced following D2-like receptor activation with the D2 agonist, quinpirole in rat brain. Unanesthetized rats were infused intravenously with 14C-DHA one minute after saline or quinpirole infusion, and serial blood samples were collected over a 20-minute period to obtain plasma. The animals were euthanized with sodium pentobarbital, their brains excised, coronally dissected and subjected to autoradiography. Plasma labeled and unlabeled unesterified DHA concentrations were measured. The brain incorporation coefficient, k*, for DHA did not differ significantly between quinpirole-treated and control rats in any of 81 identified brain regions. Conclusion: These findings demonstrate that D2-like receptor initiated signaling does not involve DHA as a second messenger, and likely does not involve iPLA2 activation. iPLA2 BETA KNOCKOUT MOUSE, A GENETIC MODEL FOR PROGRESSIVE HUMAN MOTOR DISORDERS, DEVELOPS AGE-RELATED NEUROPATHOLOGY. Calcium-independent phospholipase A2 group VIa (iPLA2 beta) preferentially releases docosahexaenoic acid (DHA) from the sn-2 position of phospholipids. Mutations of its gene, PLA2G6, are found in patients with several progressive motor disorders, including Parkinson disease. At 4 months, PLA2G6 knockout mice (iPLA2 beta (-/-)) show minimal neuropathology but altered brain DHA metabolism. By 1 year, they develop motor disturbances, cerebellar neuronal loss, and striatal iPLA2 beta;-synuclein accumulation. We hypothesized that older iPLA2beta(-/-) mice also would exhibit inflammatory and other neuropathological changes. Real-time polymerase chain reaction and Western blotting were performed on whole brain homogenate from 15 to 20-month old male iPLA2beta(-/-) or wild-type (WT) mice. These older iPLA2beta(-/-) mice compared with WT showed molecular evidence of microglial (CD-11b, iNOS) and astrocytic (glial fibrillary acidic protein) activation, disturbed expression of enzymes involved in arachidonic acid metabolism, loss of neuroprotective brain derived neurotrophic factor, and accumulation of cytokine TNF-alpha; messenger ribonucleic acid, consistent with neuroinflammatory pathology. There was no evidence of synaptic loss, of reduced expression of dopamine active reuptake transporter, or of accumulation of the Parkinson disease markers Parkin or Pink1. iPLA2 beta; expression was unchanged. iPLA2 beta; deficient mice show evidence of neuroinflammation and associated neuropathology with motor dysfunction in later life. These pathological biomarkers could be used to assess efficacy of dietary intervention, antioxidants or other therapies on disease progression in this mouse model of progressive human motor diseases associated with a PLA2G6 mutation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000134-32
Application #
9147233
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
32
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Taha, Ameer Y; Chang, Lisa; Chen, Mei et al. (2014) D2-like receptor activation does not initiate a brain docosahexaenoic acid signal in unanesthetized rats. BMC Neurosci 15:113
Rapoport, Stanley I (2013) Translational studies on regulation of brain docosahexaenoic acid (DHA) metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 88:79-85
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Ramadan, Epolia; Basselin, Mireille; Taha, Ameer Y et al. (2011) Chronic valproate treatment blocks D2-like receptor-mediated brain signaling via arachidonic acid in rats. Neuropharmacology 61:1256-64
Rapoport, Stanley I; Ramadan, Epolia; Basselin, Mireille (2011) Docosahexaenoic acid (DHA) incorporation into the brain from plasma, as an in vivo biomarker of brain DHA metabolism and neurotransmission. Prostaglandins Other Lipid Mediat 96:109-13
Basselin, Mireille; Ramadan, Epolia; Igarashi, Miki et al. (2011) Imaging upregulated brain arachidonic acid metabolism in HIV-1 transgenic rats. J Cereb Blood Flow Metab 31:486-93
Basselin, Mireille; Rosa, Angelo O; Ramadan, Epolia et al. (2010) Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)? (VIA)-deficient mice. J Lipid Res 51:3166-73

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